Acylated amino diols



Patented Mar. 13, 1951 ACYLATED AMINO DIOLS.

Loren M'. Long,.Grosse Pointe Woods, and Harvey D, Troutman, .Ferudale, Mich, assignors to Parker Davis & Company, Detroit, Mich., a cornot tion. f Michigan No Drawing, Application January 21, 1950,

Serial No. 139,957

7 Claims. (01150-9487) Wh n is. l or 2 and: B. the-same or ditierent and represents hydrogen, halogen, Intro... lower alkyl, and. lower alkoxy, radicals. The term acyl as us d in inclu e -sa urat d and 1 1 531 11.- rated lower aliphatic afiyl, halogen substituted lower aliphatic acyl, carboxy substituted. lower aliphatic acy-l, cyano. substituted loweraali-phatic acyl, ether substituted lower aliphatic. acyl, hydr y substituted lower.- alirflaatio.acvl.- ester substituted lower aliphatic acyli .benzoyl, substituted benzoyl, araliphatic. acyl, furoyl, pyridinoyl and the like.

It i lv apprec at dy those. sk lled in. the art that. the, products and ta ting materials. of. the inventioncan existin structura as well as optical isomeric forms. The term structural isomer or iorm'as. used herein refers. to the ci or trans, that is, the planar relationship of the polar groupson the two asymmetric carbon atoms. To differentiate betweenthese two possible diastereoisomers we will subsequently refer to the. cis compounds as the regular (reg, series or form and to. the. trans diast e somers a the ps ud (lb) series or form. Such cis compounds are those wherein the two most highly polar groups lie on opposite sides of the plane. of the twov carbon atoms. 1

Both the regular and pseudo forms exist as racemates ofthe optically active ,dextro (-d) and love (1) rotatory isomers aswell as in the form of the individual or separated dextro (d) and levo (1) optical isomers.

Because of the difooultyof representing tliese structural differences ingraphicformulae the customary structural formulae will be used in both the specification andclaims and anotation placed below or to the side of the formula to designate the particularstructuraland optical configuration of the compound. Wheretho formula represents the unresolved mixture oithe structural and optical isomers the notation un.

resolved will be used. However, it should be expressly understood that where no notation appears with a structural formula that the formula should be interpreted in its generic sense, that is, asrepresenting the (l) =.\p, (d) (l) =reg. or (d)=reg. isomers in separated. form as Well as the (d1) 0 or (d1) reg. optical racemates or the total unresolved mixture. of structural and optical isomers. Such a formula does-not merely represent the unresolved mixture of isomers.

In accordance with the invention acylated amino diols of the above. general formula are prepared by several different. methods. One of these methods comprises reducingacylated amide keto alcohols of the followingformula,

o NHAcyl The transformation mayv be. illustrated diagrammatically as follows:

0 NHAcyl where R and n have the same significance as given above. The reduction may be carried out using hydrogen gas in conjunction with a metal hydrogenation catalyst or by the use of nascent hydrogen generated in the reaction mixture by the interaction of a metal with an acid, lower aliphatic alcohol, water, or mixtures of the same. In carrying out the hydrogenation by catalytic means, hydrogen pressures ranging from 25 to 4000 lbs/sq. in.- and temperatures below about C. can be used. However, in order to lessen hydrogenolysis of the product it is preferable to keep the temperature and pressure as low as possible. A temperature of about 25 to- 45 C. and pressure ofabout 40 to 1000 lbs/sq. in. are usually sufficient to bring about reduction within a reasonable time and hence are preferred. 7 Some examples of the hydrogenation catalysts which can be employed are Raney nickel, palladium, palladium oxide, platinum, platinum oxide and the like. Suitable solvents for the reduction include lower aliphatic alcohols and aqueous solutions of the same, lower aliphatic acids, dioxane-water mixtures and the like. When using the nascent hydrogen method of reduction, metals or alloys such as sodium, potassium, calcium, sodium amalgam, potassium amalgam, iron, and the like are caused to react with the solvent used for the reaction to produce hydrogen in the reaction mixture. some examples of the solvents which may be used are lower aliphatic alcohols such as methanol, ethanol, propanol; lower aliphatic acids, such as acetic acid and aqueous mixtures of either lower aliphatic alcohols or acids; moist dialkyl others such as diethyl ether and lower aliphatic alcohol-acid-water mixtures. Specific combinations of these metals and solvents which have been found to be particularly effective in bringing about the' reduction of the ketonic compounds are sodium, potassium, or calcium and absolute ethanol or methanol; sodium or potassium amalgam in moist ether, ethanol or acetic acid; and iron in dilute ethanol containing acetic acid. Although either of the foregoing methods of reduction can be used with about equal success in most instances, there are, of course, instances where such methods of reduction cannot be employed. For example, where the prodi uct of the invention to be reduced contains a nitro substituent in the phenyl ring, the desired product must be obtained by one of the following methods of preparation. These methods of preparing the products of the invention consist in the acylation of acylamido alkane diols of the following formula,

' OH NHAcyl H- n-cmon on NH: akes-onion In carrying out the acylation under substantially anhydrous conditions with an acyl anhydride the reaction mixture is heated at about 60-135 C. for a short period of time. In most cases the reaction mixture need only be heated for about five to thirty minutes. If desired the reaction can be carried out at lower temperatures by allowing the reaction to proceed for a proportionately longer period of time. In general, however, the reaction is preferably carried out at about 70-100 C. for about one-half hour. When an acyl halide is used as the acylating agent under substantially anhydrous conditions and in the absence of a catalyst, the reaction is carried out at a temperature below about 50 0. As a precaution against side reactions, it is preferable to use only a slight excess of the acyl halide over that required for reaction with the terminal hydroxyl group and, in the necessary instances, the amino group. When the alkaline catalyst is used in conjunction with either an acyl halide or anhydride, the reaction can be carried out at lower temperatures and within a shorter time. In general, the quantity of acylating agent should not be much in excess of that required to react with the terminal hydroxyl group and, where a free amino diol is used as the starting group, with the amino group. The preferred temperature for the reaction ranges from 20-35 0. although the mixture can be heated to as high as C. if desired.

If an alkaline catalyst is employed the acylation can be carried out using an acyl halide and an aqueous medium at a temperature between about 0-35 C. As in some of the previously described modifications of the present acylation process, it is preferable to use only the theoretically required amount. When the acyl groups are of atype which are readily hydrolyzed, such as lower aliphatic acyl groups, the alkaline catalyst should be a relatively weak alkaline substance such as barium carbonate, calcium carbonate, magnesium carbonate, sodium acetate or the like; however, where the acyl groups are of the type more resistant to hydrolysis, such as benzoyl or substituted benzoyl radicals, strongly alkaline catalysts such as sodium hydroxide and the like may be employed. Some specific examples of the alkaline materials which may be used in the above described acylation processes are sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate, calcium hydroxide, calcium carbonate, barium carbonate, magnesium carbonate, barium hydroxide, pyridine, triethylamine, quinoline, N- ethyl morpholine, N-methyl piperidine, and the like.

As pointed out above, the amino diols of the invention and their acylated derivatives can exist in structural as well as optical isomeric forms. Where a particular optical isomeric form or optical racemate of one of the two structural forms of these products is desired, it is necessary to separate the unresolved amino diol or acylated amino diol into its two component structural isomers. This is accomplished quite readily and completely by utilization of the differences in solubility of the two forms in water, organic solvents or in water-organic solvent mixtures. Some of the organic solvents which can be used in this fractional crystallization or solubilization are lower aliphatic alcohols, acetone, chloroform, ethyl acetate and the like. In some cases, the solvent solubility differential of the two forms is not great enough to afford a clean-cut separation of the two structural isomers and in these cases it is preferable to convert the isomer mixture of the free amino diol or acylated amino diol into another acylated derivative of the amino diol whose structural isomers difier more markedly in their solubility characteristics. The structural isomers of this new acylated amino diol can then be separated by fractional crystallization and the appropriate structural form of the product so obtained converted either by acylation or hydrolysis to the desired structural form of the free amino diol or acylated amino diol.

Where a particular optical isomer of the amino diol or acylated derivative thereof is desired the corresponding individual regular or pseudo structural form of the l-naphthyl-2-aminopropane- 1,3-diol is resolved into its optical isomers via an optically active acid addition salt. This resolution which must be carried out on the free amino diol is performed by forming an acid addition salt of the racemic amine with an optically active acid such as (d) -tartaric, (1) -tartaric, (d) mandelic, (l) -m-andelic, (d) -bromcamphor sulionic, (D-bromc'afi fihor stilfonic, (d)-camphor sulfonic (ll camphcr sul-fonie separ ating the -two isom'eric-salts i lcy recrystallization fr-em; a

solventzsuch as a l'oweraliphatic alcohol er mixtu'res f the :same With- -WB:EBI' QI other' or' anic Tsolvents then regenerating thezindividu a1 1 cpticalisomers from the separatedaopticallyactive acid -addition 'salts Thy'neutralizingreachone separately; when carryihg =out 'tlfiis' resolution it is desirable, but not absolutely necessanwto choose the form of the opticallyactive acid so that the desired optical'isomer will separate from the crystallization solutifiirfii'st;

The prodfict's of the inveiition are valuable I intermediates for theapreparatieri of other organic compounds 'ii josse's'sing antibiotic activity.

' The invention isillustrated bythe"-followin examples:

Example 1 10 g. of (dl) ip l l haiilithyl)-2 aminopropane-1,3-diol is hatedwith 'an excess of acetic anhydride at 70 C. for fifteen minutes. ,Theaeaction 'ihi'xtiir' is 'vapsrateajto dryness 'ih'i a'cuo m the residue recrysta' iizea Irena thaiiel. white erys'tauinesoiid 'thiisdbtaihedlis 1) 0 '1 {"(1 --"riaphtliil) e-acefiasiido-s-aaetsxysrc- 'fiai'ie-i-ol of f 6rhiula,

:cH-dH-dmo -e-m Evaporation of the mother liquors jandre'crys'tallization of the residue yields the (db -rfeg. form. Example 3 5 g. of (dl)--,b-l-(4 nitrc l-naphthyl)-2-dichlproacetamidopropahdiol is heated at 80 '62 0 =ea siaaceuean ri 'dride anithen the reaction mixture is} was "orated'todiyness i- The 'e'sidfi til-v5 c nide-i ihtliylf faid treat amide-*3 a'cetsxyprosane iafl is purified by resrystamaa ha r tion from ethanol. "ffifihula of thi product (dl)-r11 Form ""E'icample 4 8 g. of (dl) 1-(4-nitro-1-naphthyD-2- aminopropane-Lii-di'ol is heated with an excess of dichloroacetic-anhydride eat-710 C. for fifteen minutes. The reaction mixture is evaporated to dryness in 'vacuo {ail'd the residue recrystallized from ethanoal. The white crystalline product thus obtained is (dl) l/-l-(4-nitrcr-1-naphthyl)- 2 dichloroacetamido -3-dichloroacetoxypropane- 1-01 of the formula,

461W worm Example 5 10 g. of (dl) 11-1 l initro-hnaphthyl) -2-aminopropane-LQ-didl is heate with an excess of acetic "anhydride 'at-"i0='cii'rcr fifteen minutes. The reaction mixture is evaporated to dryness in vacuo and the residue recrystallized from ethanol. The white crystallihe product thus obtained is (d1) 0-1-(4-nitro hnaphtliyl)-2 acetamido-3-acetoxypropane-l-ol of the formula,

Exam le 8 'A mixture-consisting o'ifz "gsar xa '(4-inethoxy 2-na15htli3i) -2-'cyahoa'ct pane-LS-diol and 41.4 :g; o f imam an'fiya 1 6 cc. of dry iijr'ridihe is heated for use. on the steam bath. The reaction mixture 'is diluted with cc.-o--2 N hydrochloric acid, the precipitated solid is collected,- and washed with sodium bicarbonatesdlution ahd then with water. Recrystallization from ethyl acetate yields the desired (dl) -regI-' 1K FinethliiZyQ-naphthyl) -2 cyanoacetaniido 3 furoyloxypropzthef1=ol of the formula, f I

ates-Q24 OH NH--AJE-CH;

E-CH-CHgO-F-CHzOCHI (dl)-1p Form 2 g. of the carbobenzoyloxylactamido derivative prepared above is dissolved in 30 cc. of glacial acetic acid and reduced catalytically in the presence of palladium oxide. The catalyst is removed by filtration, the filtrate evaporated to dryness in vacuo and the residue crystallized from ethanol to obtain the desired (dl) --1-(3,6- V

dichloro-l-naphthyl) -2-lac tamido 3 methoxyacetoxypropane-l-ol of the formula,

' r1:- n-cmofoomocn G1 I O1 (dl)-1,9 Form Example 8 25 g. of 5- -ethyl-1 -na.phthyl a-benzamido-ebenzoyloxyethyl ketone is dissolved in 500 m1. of ethanol and 2.5 g. of Raney-nickel hydrogenation catalyst is added. The mixture is shaken with gaseous hydrogen under about 50 lbs/sq. in. pressure for three to four hours at room temperature. The catalyst is removed by filtration, the filtrate heatedto boiling and mixed with a half volume of hot water. The (dl)-ill l-(fi-ethyl-l-naphthyl) -]2-benzamido-3-ben;zoyl- 'oxypropane-l-ol which separates from the cool solution is collected and purified by recrystallization from ethanol. The formula of this product is,

OH Nil- 10 LHin-QEd-E-Q 10.11. I, (dl)-g0 Form I If desired, the corresponding (dl) -reg. isomer which is more soluble may be recovered from the aqueous ethanolnflltrate,

Example;

too. of phenylacetyl chloride isadded in small portions to'a'suspension of 2.0 g. of (dl) -r'eg'.-'l'- (6-iodo- I-naphthyl) -2-aminopropane-l,3-diol in 30 cc. of l N sodium hydroxide solution. After a short time the precipitated solid'is collected and purified by recrystallization from methanol to obtain the (dl) reg. 1 (6 iodo 1 naphthyl) 2 phenylacetamido 3 phenylacetoxypropane-l-ol of formula, 3

(dl)-Reg. form Example 10 5 of p' -toluyl chloride is added in small portions to a suspension of 5.5 g. of (d1) -reg.-1-(l,8-

dibromo 2 naphthyl) 2 nicotinamidopropane-1,3-diol in 25 cc. of 1 N sodium hydroxide solution with shaking. Afterthe odor of p toluyl chloride has disappeared, the solid product is collected and purified by recrystallization from methanol. The product thus obtained is (dl)- reg. 1 (1,8 dibromo 2 naphthyl) 2 nicotinamido 3 p toluyloxypropane 1 c1 of formula,

N I v o Br Br on N3 4;

LH .LH CH.O CH.

' (dl)- Reg. form Emalmple 11 lo g. of 7-ethoxy-1-naphthyl a-succinamido-psuccinoyloxyethyl ketone is dissolved in 400 cc. of ethanol, and 2.2 g. of Raney nickel hydrogens ation catalyst is added. 7 The mixture is shaken with gaseous hydrogen under about 50 lbsQ/sq. in. pressure for three to four hours at room temperature. The catalyst is removed by filtration, the filtrate heated to boiling and mixed with a half volume of hot water. The (dl) l -'1-(7-ethoxy- 1 naphthyl) 2 succinamido 3 succinoyloxypropane-l-ol is collected and purified'by recrystallization from ethanol. .The formula of this product is,

3 g. of crotonyl chloride is-added to asolution of -2 .g. of (dl) -r eg.-1-(l-naphthyl) -2-aminopropane-1,3 -diol in 5 cc. of dry pyridine and the mixture allowed to stand for-24 hours. Thesolution is diluted with 35cc. of 2 N hydrochloric no go -the lolli -rikmanmhyl .f 7 $21 V m .Eazamzale 143 CH3 O iallepe w H0110 alkaline condensation catalyst 1 News 32 I 1'4: .LL

& separation via irii'cfioriall crystallization .7 v Naphthyl acylamido diols gqygolgioi (db-reg. or (dD-wl: form v.0 Nli Acyl o (Jl1 -QHzOAoyl I. T U D i hydrolysis and resolution v ia optically active acid 91k? 4 Emampleg 10 g. of4,6 dimethy1-2-na phtl1y1 a-propionamido-,3-nicoti1ioy1oxyethy1 ketone is dissolved in 200 cc. of ethanol, and 1 g. of Ragey iokelhydro- ,5

:J' /;-1- 1 -naphthy1) the starting material used in Example 1, can be prepared as follows:

ia) 60 g. of l-naphthyl acetamidom'ethyl ketone; ismixed with 300 cc. of methanol and 75 cc.-

is collected and purified by recrystallization from ethyl acetate.

(b) A mixture consisting of 53 g. of 1-naphthy1 a-acetamido-fi-hydroxyethyl ketone, 75 g. of aluminum isopropylate and 1 liter of isopropanol is heated under reflux in an atmosphere of nitrogen for about five hours. During the refluxing period the acetone which has formed is distilled off from the mixture. The isopropanol is distilled from the reaction mixture under reduced pressure and the residue treated with about 1 liter of water. The mixture is heated to boiling to insure complete precipitation of the aluminum hydroxide, filtered while hot and the filtrate allowed to cool. The (dl)'--1-(1-naphthyl) -2-acetamidopropane- 1,3-dil which separates from the cooled solution is collected by filtration and purified by recrystallization from diluteethanol The fomula of this product is, I

If desired, additional quantities ofthe (d1) 0- strutural isomer and al'so the corresponding (d1) reg. ,-1 -.(1 -naphthyl) 2 i aetamidopropane-LS- diol may be recovered from the aqueous filtrates by saturation of the filtrate with salt, exhaustive extraction with ethyl acetate; and followed by distillation of the ethyl acetate from the extract; The residue which consists of a mixture of the two structural forms is separated by crystallization from water or dilute ethanol. '(c) 25 g. of (d1) l/ 1 (1 naphthyl) -2-acetamidopropane-l,3-diol is heated with 600 cc. of "hydrochloric acid for twelve hours. The reaction mixture is cooled and the hydrochloric salt of (d1)-\,b-l-(1-naphthyl)-2-aminopropane 1-,3-diol which separates collected and washed with a small amount of water. The hydrochloride salt thus obtained is dissolved in water or suspended therein and the mixture treated with an excess of concentrated ammonium hydroxide. The (d1) --l-(1-naphthyl) -2-aminopropane-'1',3- diol free base which separates is collected, washed with a small amount of water and purified by re- 2 4 aminopropane 1,3 diol,

.12 crystallization from'water. The formula of this: product is, I

on NB:

(d) 5 g. of (dD- b-I-(I-naphthyl)-2aminopropane-1,3-dio1 is dissolved in a minimum amount of water containing a small amount of methanol and the resulting solution is treated with an aqueous solution containing an equivalent amount of (d) -tartaric acid. The solution is evaporated to dryness in vacuo and the residue fractionally crystallized from a minimum amountof hot methanol. The first isomer to separate from the solution in crystalline form is the (d)-tartaric acid salt of (l) -1, /-1-(l-naphthyl) 2 aminopropane- 1,3-diol. The (d) -tartaric acid salt of (amp-1- (l-naphthyl) -2-aminopropane-l,3-diol is recovered from the filtrates after removal of the salt of the (l) -isomer. V 7

The (d) -tartaric acid salt of (l) -1-(l-naphthyl) -2-aminopropane-1,3-diol obtained above is dissolved in water, the solution made alkaline to pH 9 with sodium hydroxide solution and the precipitated (1) -i//-1-(1-naphthyl) -2-aminopropane- 1,3-diolfreebase collected. The formula of this product is.

' 0H NH:

H-JJH-CHaOH By decomposing the (d) -tartaric acid salt of (d) -\//-'1-(1-'naphthyl) 2 -aminopropane-1,3-diol in the same manner as described above for the ..(l) -.ison 1er one obtains the free base of (d) 11-1- "consisting of isopropanol or n-butanol rather 1 lization of the tartrate salts.

The naphthyl a-acy1amido-;8-acyloxyethyl ketones used asstarting materials in the practice of this inventionmay be prepared according to the following examples. For instance, 6-methyl-2- naphthyl a-p-toluylamido-fl-acetoxyethyl ketone, the starting material in Example 2 is prepared as follows:

20 g. of 6-methyl-2-naphthyl a-(p-toluylami do) -fl-hydroxyethy1 ketone is heated at about C. for one-half hour with 40 cc. of acetic anhdyride containing a very small amount of concentrated sulfuric acid. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from methanol or ethanol. The'product thus obtained is 6-methyl-2-naphthyl e-(p-toluylamido) -p-acetoxyethyl ketone of the formula,

Jt- Balance-0H;

13 14 What we claim is: 4. A compound of formula, 1. A compound of formula, 0H NHAcyl 0H NHAcYl 311- n-cmoAc i R I- H- H-GHzOAcyl where n is one of the integers 1 and 2 and R is a N0: member of the class consisting of hydrogen, halo- 10 gen, nitro, lower alkyl and lower alkoxy radicals. 2 5 mtro'l'naplhflllyl) 2' A compound of formula, ace ami o- -ace oxypropane- -o 6. (d1) l/-1-(4 nihro-l-naphthyl) -2-dich1oro- OH NHAcYl acetamido-3-dich1oroacetoxypropane-1-01.

11- n-omoAc l 15 7. (d1)-\//-1-(4 nitro-l-naphthyl)-2-acetamido-3 acetoxypropane-l-ol.

LOREN M. LONG. HARVEY D. TROUTMAN.

No references cited. 3. (d1) 1 (l-naphthyl) 2 acetamido-3- acetoxypropane-l-ol. 

6. (DL)-$-1(4-NITRO-1-NAPTHYL)-2-DICHLOROACETAMIDO-3-DICHLOROACETOXYPROPANE-1 -01. 